US20080194525A1 - Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof - Google Patents

Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof Download PDF

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US20080194525A1
US20080194525A1 US11/913,695 US91369506A US2008194525A1 US 20080194525 A1 US20080194525 A1 US 20080194525A1 US 91369506 A US91369506 A US 91369506A US 2008194525 A1 US2008194525 A1 US 2008194525A1
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acid
salt
bisphosphonic
bisphosphonic acid
anhydride
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Jordi Puig Serrano
Jordi Bosch Illado
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Medichem SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates to the process of making geminal bisphosphonic acids and pharmaceutically acceptable salts and/or hydrates thereof which have the formula:
  • bisphosphonates have been studied for use in the treatment of Paget's disease and hypercalcemia but much interest has concerned their role in the treatment of osteoporosis (e.g. alendronate (FOSAMAX®).
  • Other previously known bisphosphonates include clodronate, etidronate, etidronate sodium, ibandronate, pamidronate, risedronate, tiludronate and zoledronic acid.
  • risedronic acid and its pharmaceutically acceptable salts are described in U.S. Pat. No. 5,583,122. No examples for the preparation of specific risedronic acid or its pharmaceutically acceptable salts are included.
  • a method for obtaining 2-(2-pyridyl)-1-hydroxy-ethane-1,1-diphosphonic acid, an isomer of position of risedronic acid is described. The method makes use of a mixture of phosphorous acid and phosphorous trichloride, as bisphosphonation mixture, in chlorobenzene.
  • the crude bisphosphonic acid is obtained from a mixture of water and methanol and then is recrystallized from hot water.
  • Example 3 of U.S. Pat. No. 5,391,743 refers to a preparation of risedronic acid.
  • a mixture of 3-pyridylacetic acid hydrochloride, phosphorous acid and phosphorous trichloride is refluxed at 100° C. in the presence of chlorobenzene and a gummy oil is formed.
  • the chlorobenzene is decanted and the gummy oil is hydrolyzed in 1N HCl.
  • the obtained crystals are then filtered.
  • the filtrate is evaporated to an oil and a small amount of water is added to dissolved the oil.
  • ethanol is added to induce crystallization.
  • the two crops of solids obtained are recrystallized from hot water. No characteristics of the obtained product are mentioned.
  • EP 1 243 592 A refers to a process for the preparation of risedronic acid by refluxing/heating a mixture of 3-pyridylacetic acid, phosphorous acid and phosphorous trichloride in the presence of a halobenzene (chlorobenzene or fluorobenzene), decanting the halobenzene, refluxing the reaction residue with NaOH, and adding concentrated HCl. The solid is filtered and washed with ethanol and dried at 80° C.
  • a halobenzene chlorobenzene or fluorobenzene
  • Examples 1 and 2 of U.S. Pat. No. 6,562,974 (equivalent to EP 1 252 169 B1) refer to a process for obtaining risedronic acid.
  • the reaction is performed by heating a mixture of 3-pyridyl acetic acid or its hydrochloride, phosphorous acid and phosphorous trichloride in the presence of a cyclic amine or its hydrochloride salts.
  • the reaction is hydrolyzed by heating it with aqueous hydrochloric acid.
  • the crude risedronic acid is recrystallized from aqueous acid/isopropanol. No characteristics of the obtained product are mentioned.
  • WO 03/093282 refers to a process for obtaining bisphosphonic acids using a bisphosphonation mixture of acids and phosphorous trichloride characterized in that the reaction is conducted in ionic liquids as the reaction solvents.
  • example 2 refers to a preparation of risedronic acid when using the appropriate starting material.
  • Examples 1-10 of WO 03/097655 refer to a process for obtaining crystalline risedronic acid monohydrate although any characteristics of the obtained product is mentioned.
  • the process makes use of a bisphosphonation mixture phosphorous acid and a selected halophosphorous compound in the presence of a diluent that is an aromatic.
  • the risedronic acid is obtained from a mixture of water and ethanol.
  • This document refers to a method to avoid solidification of the mixture which includes the use of ortho-phosphoric acid or poly(dimethysiloxane) as a codiluent or, alternatively, the use of diatomite silica as a solid support.
  • WO 04/067541 refers to a process of obtaining risedronic acid monohydrate using a bisphosphonation mixture of phosphorous acid and phosphorous pentoxide in the presence of methanesulphonic acid. The product is obtained by recrystallization from water.
  • WO 05/012314 refers to the preparation of risedronic acid sodium salt in its hemipentahydrate form by adjusting the pH of solution of risedronic acid in a mixture of water and isopropanol.
  • Examples 1 and 2 of U.S. Pat. No. 6,410,520 refers to a first preparation of risedronate monosodium salt in the form of its hemipentahydrate or in the form of its monohydrate by adding a selected solvent over an aqueous solution of risedronic acid sodium.
  • the obtained risedronic sodium salts hemi-pentahydrated and monohydrated have been characterized by X-ray powder diffraction, thermogravimetric analysis, DSC, FT-IR and NIR-IR, however no characteristics are included in this patent.
  • the present invention endeavors to address problems of prior processes for preparing bisphosphonic acids
  • bisphosphonates such as:
  • the present invention relates to a novel process for making geminal bisphosphonic acids and their pharmaceutically acceptable salts.
  • the process of the invention provides a novel bisphosphonation method advantageously characterized by using a mixture comprising or consisting essentially of phosphorous acid and a phosphonic anhydride such as propylphosphonic anhydride (also known as 1-propanephosphonic anhydride or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide).
  • the process of the invention also provides a novel bisphosphonation method advantageously characterized by use of an agent comprising or consisting essentially of methanesulfonic anhydride.
  • the process of the invention additionally provides a novel bisphosphonation method advantageously characterized by use of a mixture comprising or consisting essentially of methanesulfonic anhydride and phosphorous acid.
  • bisphosphonation is the chemical reaction resulting in the production of a product containing two phosphonic acid groups on the same carbon (geminal bisphosphonic compounds).
  • the geminal bisphosphonic acids made by this process are 1-hydroxy-2-(3-pyridinyl)ethylidine bisphosphonic acid (risedronic acid), 4-amino-1-hydroxybutylidene-1,1-bisphonic acid (aledronic acid), 3-amino-1-hydroxypropylidene-diphosphonic acid (pamidronic acid), [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bisphosphonic acid (zoledronic acid) and [1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]-bisphosphonic acid (ibandronic acid).
  • the geminal bisphosphonic acid is risedronic acid, 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid.
  • propylphosphonic anhydride represents a surprising and unexpected improvement when compared with the known methods for the synthesis of bisphosphonates.
  • the term “industrial scale-up” defines a process which produces geminal bisphosphonic acid in amounts selected from the ranges of greater than about 100 g, greater than about 1 kg, and greater than about 100 kg; and the term “substantially solution form” defines that the reactants/reaction mixture have a solids content selected from the ranges of less than about 10% w/w, less than about 5% w/w and less than about 1% w/w.
  • FIG. 1 depicts the X-ray powder diffractogram of risedronic acid obtained in Example D3.
  • FIG. 2 depicts the X-ray powder diffractogram of risedronate sodium hemipentahydrate obtained in Example 1.
  • the present invention relates to a novel process for making geminal bisphosphonic acids and their pharmaceutically acceptable salts.
  • the process provides for bisphosphonation using a mixture of phosphorous acid and a phosphonic anhydride such as propylphosphonic anhydride (also known as 1-propanephosphonic anhydride or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide).
  • a phosphonic anhydride such as propylphosphonic anhydride (also known as 1-propanephosphonic anhydride or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide).
  • Preferred geminal bisphosphonic acid include but are not limited to clodronic acid, etidronic acid, ibandronic acid, pamidronic acid, residronic acid, tiludronic and zoledronic acid.
  • Particularly preferred geminal bisphosphonic acids made by this process are 1-hydroxy-2-(3-pyridinyl)ethylidine bisphosphonic acid (risedronic acid), 4-amino-1-hydroxybutylidene-1,1-bisphonic acid (aledronic acid), and 3-amino-1-hydroxypropylidene-diphosphonic acid (pamidronic acid), [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bisphosphonic acid (zoledronic acid) and [1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]-bisphosphonic acid (ibandronic acid). Most preferred is risedronic acid, 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid.
  • the process of the present invention for making geminal bisphosphonic acids and their pharmaceutically acceptable salts involves the phosphonation of a mixture which consists of a compound of the formula R 1 —C( ⁇ O)—R 2 , phosphorous acid and an alkylphosphonic anhydride and optionally a pH adjustment to form the appropriate salt or hydrate.
  • This process is easily adaptable to industrial application with good yields and does not require the use of reactants such as PCl 3 , PCl 5 or POCl 3 , which are highly toxic and hazardous for the environment.
  • reactants such as PCl 3 , PCl 5 or POCl 3
  • Pharmaceutically acceptable salts with bases include but are not limited to alkali metal salts (including but not limited to sodium salts or potassium salts), alkaline earth metal salts (including but not limited to calcium salts or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethyl amine, triethlyamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
  • the pharmaceutically acceptable salt form is a sodium or potassium salt.
  • an additional inert solvent is optional. Although it is not necessary, the bisphosphonation reaction is advantageously conducted in the presence of inert solvents.
  • An inert solvent is understood to be one which does not react substantially with the reactants involved.
  • Preferred among the inert solvents are an aprotic solvent such as aromatic hydrocarbons (such as xylene, toluene, etc), organic acetates solvents (such as ethyl acetate, isopropyl acetate, etc), ketonic solvents and mixtures thereof. Particularly preferred are toluene and ethyl acetate.
  • the invention relates to a process for the preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (risedronic acid) and its pharmaceutically acceptable salts.
  • the process consists of reacting 3-pyridyl acetic acid in its free base form or as a hydrohalide salt with a phosphonation mixture formed by phosphorous acid and propylphosphonic anhydride (also known as 1-propanephosphonic anhydride or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide), and thereafter hydrolyzing the bisphosphonation mixture and the product of said bisphosphonation reaction and isolating directly, by an appropriate pH adjustment, if necessary, the free acid or the sodium salts.
  • a phosphonation mixture formed by phosphorous acid and propylphosphonic anhydride (also known as 1-propanephosphonic anhydride or 2,4,6-tripropyl-1,3,5,2,4,6-
  • the corresponding pharmaceutically acceptable salt may be obtained by treating a suspension or a solution of the bisphosphonic acid with a base.
  • the 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid may be obtained by neutralizing a solution or suspension of the salt with an acid stronger than the 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid itself, for example, hydrochloric acid, sulfuric acid, etc.
  • R 1 and R 2 are independently hydrogen, hydroxy or alkyl which is substituted or unsubstituted.
  • R 1 is hydroxy and R 2 is a substituted or unsubstituted C 1 -C 4 -alkyl; in yet another embodiment of the invention, R 1 is hydroxy and R 2 is a C 1 -C 2 -alkyl.
  • the substitution is at least one moiety selected from the group consisting of amino, aryl or N-containing heteroaryl.
  • the heteroaryl is selected from the group consisting of, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl and triazinyl.
  • the N-containing heteroaryl is pyridinyl or imidazolyl.
  • the alkylphosphinic anhydride is a C 1 -C 8 -alkylphosphinic anhydride. In yet another embodiment of the invention, the alkylphosphinic anhydride is a C 1 -C 4 -alkylphosphinic anhydride. In still another embodiment of the invention, the alkylphosphinic anhydride is propylphosphonic anhydride.
  • alkyl is generally a straight chain or branched chain unsubstituted or substituted C 1 -C 12 carbon chain, or a cyclic C 3 -C 12 substituted or unsubstituted carbon ring, advantageously a straight chain or branched chain unsubstituted or substituted C 1 -C 8 carbon chain or an unsubstituted or substituted C 3 -C 8 carbon ring, for instance, a straight chain or branched chain unsubstituted or substituted C 1 -C 6 carbon chain or an unsubstituted or substituted C 3 -C 6 carbon ring, e.g., a straight chain or branched chain unsubstituted or substituted C 1 -C 5 or C 1 -C 4 carbon chain, such as a straight chain or branched chain unsubstituted or substituted C 1 -C 3 or C 1 -C 2 carbon chain.
  • Aryl is typically an unsubstituted or substituted C 5 to C 12 membered aromatic ring, such as phenyl or tolyl or xylyl. If the alkyl group comprises more than one C then those carbons need not necessarily be linked to each other. For instance, at least two of the carbons of an alkyl may be linked via a suitable element or society. g., the alkyl chain or ring or an aromatic ring of an aryl may hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen.
  • Suitable substitutions on carbon chains or rings include halo, e.g., F, Cl, Br, I, alkoxy, nitro, an alkyl group, a cyclic group such as a cyclo-alkyl or aryl group.
  • halo e.g., F, Cl, Br, I
  • alkoxy nitro
  • an alkyl group e.g., F, Cl, Br, I
  • alkoxy e.g., a cyclic group
  • a cyclic group such as a cyclo-alkyl or aryl group.
  • the size of alkyl and aryl groups and substituents therein or thereon should be non-interfering or minimally interfering as to the inventive process.
  • Appropriate temperatures for the bisphosphonation reaction is selected from the range of from about 35° C. to about 125° C. and from about 65° C. to about 95° C.
  • the mixture is stirred at the required temperature for the required time.
  • the bisphosphonation reaction is interrupted by the addition of water at a temperature selected from the range from about 0° C. to about 90° C., preferably from about 0° C. to about 40° C. to hydrolyze unreacted bisfosphonation mixture.
  • a temperature selected from the range from about 0° C. to about 90° C. preferably from about 0° C. to about 40° C. to hydrolyze unreacted bisfosphonation mixture.
  • the organic layer is preferably decanted and separated.
  • the resulting aqueous mixture is heated to a temperature above about 50° C., preferably to the reflux temperature of said mixture, to ensure complete hydrolysis.
  • One embodiment of the process for preparing risedronic acid and/or hydrates thereof according to the invention comprises the following steps:
  • the process in one embodiment, about 3 moles of phosphorous acid are used and about 2.5 moles of propylphosphonic anhydride (6:5 ratio) are used. In another embodiment of the experiments using about 2.5 moles of phosphorous acid and about 1.5 moles of propylphosphonic anhydride (5:3 ratio) also gave an acceptable yield.
  • the reactants may be added to the reaction vessel and the mixture heated up to react (batch mode reaction) or, in another embodiment of the invention the propylphosphonic acid solution is added stepwise into the reactor vessel containing the rest of the reactants and a convenient amount of the convenient solvent (semi-batch mode).
  • the semi-batch mode is more convenient since the thermal response of the reaction may be addition controlled.
  • the semi-batch mode is characterized for the addition time.
  • a convenient addition time is between about several minutes to about several hours. In one embodiment of the addition time, the time is between about 5 to about 15 hours.
  • the pyridine-3-yl acetic acid hydrochloride can be reacted with methanesulfonic anhydride or methanesulfonic acid and phosphorus acid,
  • the bisphosphonic acids and/or hydrates thereof formed by the described process results in a yield of at least about 70%; in another embodiment of the invention, the yield is in the range of about 70% to about 90.%.
  • the chromatographic purity of the bisphosphonic acids and/or hydrates thereof formed by the described process is at least 99.00%; in another embodiment of the invention, the chromatographic purity is about 99.25% to about 99.6%
  • the bisphosphonic acids formed by the process described above can further be treated to form the corresponding salt and/or hydrate form thereof.
  • the process for converting bisphosphonic acid or its hydrated forms thereof to its salt thereof comprises:
  • the process for converting bisphosphonic acid or its hydrated forms thereof to its salt thereof comprises:
  • the organic amine is an arylamine or a mono-, di- or tri-alkylamine.
  • the alkyl length of the mono-, di- or tri-alkylamine is C 1 -C 8 ; in yet another embodiment of the invention the alkyl length of the mono-, di- or tri-alkylamine is C 1 -C 4 .
  • compositions containing the hemipentahydrate or the monohydrate forms of monosodium salt of bisphosphonic acid or mixtures thereof are pharmaceutical compositions containing the hemipentahydrate or the monohydrate forms of monosodium salt of bisphosphonic acid or mixtures thereof.
  • the salts of the bisphosphonic acids or hydrated form thereof formed by the described process results in a yield of at least about 70%; in another embodiment of the invention, the yield is in the range of about 75% to about 85%.
  • the chromatographic purity of the salts of bisphosphonic acids or hydrated form thereof formed by the described process is at least 99.50%; in another embodiment of the invention, the chromatographic purity is about 99.7% to about 99.9%.
  • Procedures B, C and D, as described herein, provide synthetic alternatives that have increased safety and are more environmentally friendly in comparison to the other methodologies currently in use.
  • roach B example B1
  • Approach B refers to an adaptation of the process of U.S. Pat. No. 6,573,401 (assigned to Medichem S.A. and which is incorporated by reference), which uses methanesulfonic anhydride instead of the phosphorous halides.
  • the third approach is the “combined” approach (approach C, examples C1 and C2) and it describes a way of avoiding solidification by using methanesulfonic anhydride together with phosphorous halides.
  • methanesulfonic anhydride plays the double role of dehydrating agent and stirring enhancer.
  • the fourth approach (approach D, examples D1 to D4) describes the propylphosphonic anhydride approach.
  • the procedure depicted is a cleaner, environmentally friendly methodology that appears to be easy to scale up and which uses materials that are easier to handle than the phosphorous halides. There are no solidification problems during the reaction, yields are high, reaction times affordable and the reaction is simple to work up.
  • the target risedronate monosodium salt hemipentahydrate is obtained in a procedure comprising:
  • the solution or resulting mixture can be optionally treated with a decolorating agent and is filtered in order to separate insoluble particles.
  • compositions containing the hemipentahydrate or the monohydrate forms of monosodium salt of risedronic acid or mixtures thereof are pharmaceutical compositions containing the hemipentahydrate or the monohydrate forms of monosodium salt of risedronic acid or mixtures thereof.
  • Example 1 is a reproduction of Example 1 in WO 03/097655 A1 and exemplifies the need of a suitable process to scale up.
  • the mixture was heated to 87° C. at which point 3.23 ml (3.53 ⁇ 10 ⁇ 2 mol) of POCl 3 was added dropwise during about 20 minutes.
  • the resulting mixture was heated up to 95° C. After a few minutes at regime a sticky solid appeared, disenabling a proper stirring.
  • the mixture was kept at 95° C. 20.5 h in these deficient stirring conditions.
  • the mixture was then let to cool down to 80° C. at which point 7.2 ml of water were added dropwise (exothermy was observed).
  • the mixture was stirred at 80° C. for 15 minutes and then let to cool down to room temperature.
  • the heterogeneous mixture was heated up to 95° C.
  • the mixture was stirred at 95° C. overnight and let to cool down to 80° C. at which point 7.2 ml of water were added dropwise.
  • the resulting mixture was stirred at 80° C. for 15 minutes and let to cool down to room temperature.
  • the heterogeneous mixture was heated up to 75° C.
  • the mixture was stirred at 95° C. overnight and let to cool down to 80° C. at which point 7.2 ml of water were added dropwise.
  • the resulting mixture was stirred at 75° C. for 15 minutes and let to cool down to room temperature.
  • the aqueous phase was decanted and heated to 90-95° C. for 5.5 h. A white solid precipitated out from the mixture.
  • the mixture was stirred at reflux for 10 additional hours, at which point 200 ml of water was added in about 2 hours.
  • the mixture was hydrolyzed under reflux for about 3.5 hours, let cooled down to 5° C. and the whitish solid precipitated was filtered, the cake washed with water.
  • the chromatographic separation is carried out with an Atlantis dC18, 3 ⁇ m. 5 cm ⁇ 3.0 mm. I.D column.
  • the chromatograph is equipped with a 263 nm detector and the flow rate is 1.0 ml per minute at room temperature. Inject 20 ⁇ l of the test samples prepared dissolving the appropriate amount of sample to obtain 0.5 mg per ml of water for Risedronate samples or 0.5 mg per ml of 0.24% NaOH in water for Risedronic acid samples.
  • the chromatographic separation is carried out with an Atlantis dC18, 3 ⁇ m. 5 cm ⁇ 3.0 mm. I.D column.
  • the chromatograph is equipped with a 263 nm detector and the flow rate is 1.0 ml per minute at room temperature. Inject 20 ⁇ l of the test samples and Reference standard prepared dissolving the appropriate amount of sample to obtain 0.05 mg per ml of water, for Risedronate samples, or 0.05 mg per ml of 0.24% NaOH in water for risedronic acid samples. Calculate the amount of risedronic or risedronate by comparison of the normalized areas.

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US11/913,695 2005-05-06 2006-05-05 Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof Abandoned US20080194525A1 (en)

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US20090176913A1 (en) * 2006-05-09 2009-07-09 Adeka Corporation Polyester resin composition
US20100121066A1 (en) * 2007-06-20 2010-05-13 Ankush Tavhare M Novel Process For Preparing Risedronic Acid
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts

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US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
ES2650665T3 (es) 2009-07-31 2018-01-19 Grünenthal GmbH Método de cristalización y biodisponibilidad
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
WO2011016738A1 (en) 2009-08-05 2011-02-10 Zaklady Farmaceutyczne Polpharma Sa A process for the synthesis of 1-hydroxy-3-(n-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone
WO2012071517A2 (en) 2010-11-24 2012-05-31 Thar Pharmaceuticals, Inc. Novel crystalline forms
PL2665734T3 (pl) * 2011-01-21 2016-12-30 Sposób wytwarzania związków zawierających grupę alfa-oksyfosforową
WO2017208070A1 (en) 2016-05-31 2017-12-07 Grünenthal GmbH Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis

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US5510517A (en) * 1993-08-25 1996-04-23 Merck & Co., Inc. Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids
US6573401B1 (en) * 1999-08-06 2003-06-03 Medichem, S.A. Process for producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and its trihydrated monosodium salt
US6410520B2 (en) * 2000-02-01 2002-06-25 The Procter & Gamble Company Selective crystallization of 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid sodium as the hemipentahydrate or monohydrate

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US20090176913A1 (en) * 2006-05-09 2009-07-09 Adeka Corporation Polyester resin composition
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts
US20100121066A1 (en) * 2007-06-20 2010-05-13 Ankush Tavhare M Novel Process For Preparing Risedronic Acid

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IL187184A0 (en) 2008-02-09
EP1883644A2 (de) 2008-02-06
CA2606879A1 (en) 2007-03-01
WO2007023342A3 (en) 2007-05-03
WO2007023342A2 (en) 2007-03-01
AR057291A1 (es) 2007-11-28
ES2324015T1 (es) 2009-07-29

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